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2. The Pathophysiology of Poisonous Plant Intoxication Bryan L. Stegelmeier January 25, 2010 ADVS 5860

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5. Lecture Outline Introduction Aristolochia spp. Larkspur Definitions Mechanism of Toxicity Specific Tissue Toxicities

6. PPRL 2010 Aristolochia tomentosa

7. PPRL 2010 Germany 1950’s Endemic Uropathy 1980’s

8. PPRL 2010 $85 Billion in 2007 Unregulated (Hatch Act) Unproven efficacy or safety

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10. Aristolochia fanchi substituted for Stephania tetrandra Chinese herb ‘Mu Tong’ Weight loss herbal product

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12. 20X Incidence

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14. Recommended it be listed as a known human carcinogen Dose? Risk of exposure?

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16. Larkspur (Delphinium spp.)

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18. 5-10% Death loss

19. PPRL 2010 Larkspur Toxins

20. PPRL 2010 Striated Muscle Toxins Larkspur (MLA block AchR) Monkshood (Aconitum inhibits Na channels) Botulism (cleaves synaptobrivin, syntaxin and SNAP-25 blocking cholinergic tx) Tetnus (tetanospasmin blocks glycine inhibition) Cardioglycosides (Inhibits Na/K ATPase enzyme)

21. PPRL 2010 MLA mechanism of action

22. PPRL 2010 Knowing it is poisonous is not enough. Treatment Select resistant animals Medical applications

23. PPRL 2010 Definitions

24. PPRL 2010 Physiologic Response to Insult Molecular Response No change Molecular damage Repairable or Permanent damage

25. PPRL 2010 Tissue Responses No Change Loss of function Inflammation Rubor Calor Tumor Dolor Loss of Function Necrosis Hyperplasia Neoplasia

26. PPRL 2010 Animal Responses No change Sick- disease Attitude Appetite Weight Organ or system specific changes (Reproduction, Respiration, Cardiac Function, Hematologic Function, Immune Function, Urinary Function, Gastrointestinal Function, Musculoskeletal Function, Endocrine Function, Neurologic Function, etc) Death

27. PPRL 2010 Herd Responses Stocking Rate Economic, Emotional, and Physical Factors

28. PPRL 2010 Conclusions There are about 10-20 tissue and animal specific responses and thousands of diseases Many diseases cause similar responses; few produce specific or pathognomonic lesions.

29. PPRL 2010 Direct vs Indirect toxicity

30. PPRL 2010 Mechanisms of Action Mechanical Injury: Various grasses- barley, foxtails etc- foreign body abscesses, stomatitis, and dermatitis Cocklebur- gastric obstruction Turkey mullein (Eremocarpus setigerus) phytobezoars and phytoconcretions Oxalate crystals (Ca oxalate causing cellular damage like nephrosis)

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34. Local irritant Contact dermatitis- urushiols, Urtica spp., Stinging trees Stomatitis/Gastritis- tannins, phenolic, astringents, saponins Oxalates: Dumb cane (Dieffenbachia sequine) Proteolytics- bromelain and papain, lectins

35. PPRL 2010 Receptor mediated: AchR- Larkspur alkaloids Nicotinic AchR- Lupine, Tobacco, Conine Steroidal receptors- Veratrum ICA pine needles

36. PPRL 2010 Enzyme inhibition: Glycosidase inhibitors- swainsonine, calystegins, castanospermine Trypsin and amylase inhibitors- soybeans, peas, potatoes, barley, alfalfa Dicumarol- vitamin K antagonist Mitosis inhibition- S and prophase arrest of PA’s, metaphase arrest of lupinosis Cholinesterase inhibitors- Solanum and green potatoes

37. PPRL 2010 Antinutritional: Indospecine (arginine analog) Indospecine spicata Mimosine Selenium toxicity- Anti-trypsin, anti- amylase Thiaminase

38. PPRL 2010 Direct cytotoxity DNA/protein alkalation/adduct- denaturing Inhibit oxidative phosphoralation- Miserotoxin, Cyanogenic glycosides, fluroacetate Alter membrane permeability- digitalis Physical cellular damage- oxylates Alter anion or cation metabolism- Ca++ Ca chelation- phytic acid and oxalate Calcinogenic glycosides Cu and Zn storage Mg metabolism 3-methy-indole Cholestasis- Lantana, saponins All other tissue specific direct toxicity

39. PPRL 2010 Specific Tissue Toxicity Neurotoxic Plants 1. Locoweed 2. Yellow star thistle and knapweed 3. Larkspur 4. Hemlocks 5. Death camas 6. Bracken fern 7. Jimsonweed

40. PPRL 2010 Hepatotoxic Plants Pyrrolizidine alkaloid containing plants Tetradymia and hepatogenic photosensitization vs primary photosensitization caused by St. Johns wort or spring parsley Cocklebur Alsike clover

41. PPRL 2010 Nephrotoxic Plants Oxalate containing plants- Halogeton and greasewood Oak and other plants causing nephrosis

42. PPRL 2010 Plants with Reproductive Toxins Pinus ponderosa and broomweed Teratogens such as Veratrum, Lupine etc

43. PPRL 2010 Plants that have Gastrointestinal Toxins Pineapple (bromelain), papaya (papain) proteolytic enyzymes Enzyme inhibitors (typsin and amylase inhibitors) Dieffenbachia sequine-dumb cane, rhubarb, halogeton, greasewood, oak, phenolics, tannins Grasses/Hay (Nitrate/Nitrite, Saponins) Mustards (Brassica, Raphanus, Descurania) Castor Bean Sneezeweed (Helenium) Nightshades

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45. Plants that are Cardiotoxic or Myotoxic White snakeroot and rayless golden rod Oleander and milkweeds Thermopsis

46. PPRL 2010 Sudden Death without many lesions: Nitrates (sorghum, various grasses, oats, hay, corn, Kochia, pigweed, Russian thistle, nightshades) Cyanide (sorghum, larel cherry, arrow grass, chokecherry)

47. PPRL 2010 Reading Assignment: Cheeke “Natural Toxicants in Feeds, Forages, and Poisonous Plants” Part 1, pages 3-51